Zhang et al. manipulated red blood cells to serve as artificial antigen-presenting cells (RCT-aAPC) expressing three signals: SIINFEKL peptide on MHC-I, 4-1BBL, and a cytokine (IL-7, IL-12, or IL-15). RCT-aAPC with IL-12 most effectively stimulated OT1 expansion and EG7.OVA tumor control in vivo, also inducing endogenous T cell activation, OT1 memory responses, and epitope spreading. RCT-aAPC distributed primarily to the spleen, colocalizing with transferred OT1 cells, and led to minimal and transient systemic toxicities. RCT-aAPC expressing gp100 or E7 could activate and expand T cells specific to these antigens.
Contributed by Alex Najibi
ABSTRACT: Checkpoint inhibitors and T-cell therapies have highlighted the critical role of T cells in anti-cancer immunity. However, limitations associated with these treatments drive the need for alternative approaches. Here, we engineer red blood cells into artificial antigen-presenting cells (aAPCs) presenting a peptide bound to the major histocompatibility complex I, the costimulatory ligand 4-1BBL, and interleukin (IL)-12. This leads to robust, antigen-specific T-cell expansion, memory formation, additional immune activation, tumor control, and antigen spreading in tumor models in vivo. The presence of 4-1BBL and IL-12 induces minimal toxicities due to restriction to the vasculature and spleen. The allogeneic aAPC, RTX-321, comprised of human leukocyte antigen-A*02:01 presenting the human papilloma virus (HPV) peptide HPV16 E7(11-19), 4-1BBL, and IL-12 on the surface, activates HPV-specific T cells and promotes effector function in vitro. Thus, RTX-321 is a potential 'off-the-shelf' in vivo cellular immunotherapy for treating HPV_+_cancers, including cervical and head/neck cancers.